Faculty Directory

Valerie Hu

Education

BS, University of Hawaii, 1972

PhD, California Institute of Technology, 1977

Research

The long-term goals of my laboratory are personalized diagnosis and treatment of autism spectrum disorders (ASD). We aim to achieve these goals by developing a better understanding of the underlying biology giving rise to different manifestations of autism through the identification of altered genes, pathways, and gene regulatory mechanisms specific to the different subtypes of ASD.As shown by our published studies on individuals with ASD, we have succeeded in identifying genes, metabolic/signaling pathways, and epigenetic mechanisms (both DNA methylation and microRNA expression) involved in ASD by reducing the clinical heterogeneity among subjects for transcriptomic, genetic and epigenetic analyses. We accomplish heterogeneity reduction either by using diagnostically discordant monozygotic twins and siblings in our studies or by dividing the ASD population into more homogeneous subgroups based on similar symptomatic profiles. The latter technique has proven to be especially useful in identifying subtype-dependent gene expression differences among groups of unrelated individuals with ASD relative to controls as well as subtype-dependent genetic variants (SNPs) and linkage loci. In both expression and genetic analyses, a number of shared genes/SNPs were also identified, demonstrating some of the expected biological commonality among the ASD subtypes.Interestingly, the shared SNPs exhibited distinctly different odds ratios in the different subtypes, demonstrating that the subtypes are genetically distinct in relation to these SNPs. Thus, a systems approach to ASD using integrative genomics coupled with phenotyping of subjects has led to the discovery of novel candidate genes relevant to pathobiological processes involved in ASD as well as to the identification of potential diagnostic biomarkers at multiple levels: gene expression, microRNA, DNA methylation, and genetics.One of the novel genes identified through our studies is retinoic acid-related orphan receptor alpha (RORA) which is a nuclear hormone receptor that not only regulates many other genes that are implicated in the pathobiology of ASD, but also is oppositely regulated by male and female hormones in a manner that suggests its contribution to the male bias in ASD. Ongoing studies are continuing to examine mechanisms of pathogenesis involving dysregulation of RORA as well as gene-environment interactions that elevate risk for ASD.

Sarachara, T. and Hu, V.W. (2013) Differential recruitment of coregulators to the RORA promoter adds another layer of complexity to gene (dys)regulation by sex hormones in autism. Molecular Autism, in press.